Method of treatment of Alzheimer&#39;s disease using phytic acid

ABSTRACT

A method is provided for treating Alzheimer&#39;s Disease by administering to a subject an effective symptom-alleviating amount of a compound selected from the group consisting of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or phytate salt, or a mixture of any combination thereof. The preferred method of administration is by oral dosages of about 1/2 to 3 grams/kilogram bodyweight per day.

The present invention is directed to a method for treating Alzheimer'sDisease by use of phytic acid, its salts or hydrolysates. BACKGROUND OFTHE INVENTION

Phytic acid, generally accepted as having the structuremyo-inositol-hexakis (dihydrogen phosphate), is a major component ofplant seeds, constituting 1-3% by weight of many cereals and oil seeds.Most wheat brans contain between 4 and 5% phytic acid. Phytic acid maybe prepared in pure form from various plant sources, such as wheat,corn, soybeans, sesame seeds, peanuts, lima beans, barley, oats, wildrice and sunflower seeds. It can be extracted with dilute hydrochloricacid at room temperature, precipitated with various reagents includingferric chloride, bicarbonates, potassium hydroxide, sodium hydroxide,ammonium hydroxide, calcium hydroxide, magnesium hydroxide or alcohol.It is then further purified by conventional chemical techniques.

When one or more of the acidic protons of the phosphate groups in phyticacid are replaced by a counterion, the compound is usually referred toas a phytate salt. The special name phytin is used for thecalcium-magnesium salt of phytate derived from plant seeds (a product ofCiba-Geigy). The present invention includes the use not only of phyticacid and phytate salts, but also various isomeric forms of phytic acidand phytate salts. While the Anderson structure for myo-inositol hexakisdihydrogen phosphate is the accepted structure for phytic acid, thepresent invention covers other isomers which have been previouslydescribed in the literature. These isomers include the cis, epi, allo,muco, neo, D-chiro, L-chiro, and scyllo configurations.

Also, while phytic acid contains six phosphate groups, when introducedinto the digestive tract of an animal, one or more of the phosphategroups may be hydrolyzed by the action of the digestive acids andenzymes. Therefore, the present invention includes the use ofhydrolysates of phytic acid and phytate salts wherein one or more of thephosphate groups have been removed.

The main uses of phytic acid include use as a food additive forpreservation of foods. Studies on the use of phytic acid as a foodadditive show that ingestion of large doses of phytic acid elicits nophysiological discomfort or symptoms of any toxicological action inhumans. See Starkenstein, Biochem. Z. 30: 56 (1911). Phytic acid and itsmetabolites are thus not believed to be toxic or highly reactive.

Medical applications of phytic acid include use as an imaging agent fororgan scintography, an X-ray enhancement contrasting agent and use toreduce gastric secretion for treatment of gastritis, gastroduodenitis,gastric duodenal ulcers and diarrhea. It has been suggested as anantidote for toxic metal absorption, for therapeutic use in theprevention and dilution of calcium deposits associated with variousdiseases and for reducing calcium concentration in urine (thus checkingthe formation of renal calculi). Other uses include as a preventiveagent against severe poisoning with pressurized oxygen and preventingthirst during exercise. It has been used as a counterion in salts withvarious orally administered antibiotics to improve taste.

Phytic acid has also been suggested to reduce the incidence of dentalcaries, and has been utilized in dentifrices, mouth rinses, dentalcements, cleaning agents for dentures and for removing nicotine tar fromteeth.

Industrial uses of phytic acid include use as a corrosion inhibitor onmetals, a rust remover and an additive to lubricating greases. Othermiscellaneous uses of phytic acid include oral administration to treatacne, to improve skin color, blood circulation and fingernail growth;and as an additive in cosmetics for anti-dandruff hair lotions and skincare lotions. One potential agricultural use of phytic acid is toinhibit aflatoxin production by Aspergillus parasiticus. It is alsouseful as an additive to a fermentation medium containing Micromonosporasagamiensis in the fermentative production of antibiotics. Similarly,phytic acid may be used as a growth-promoting factor in the fermentationmedium for the cultivation of yeast for feed.

For further discussions of industrial applications of phytic acid, seeGraf, JAOCS 60, 1861-1867 (1983).

Although the above description indicates the broad scope of potentialuses of phytic acid, there is not believed to be any suggestion in theprior art that phytic acid is useful for the treatment of Alzheimer'sDisease.

Accordingly, it is an object of the present invention to provide amethod for treatment of Alzheimer's Disease by use of phytic acid,phytate salts, and isomers or hydrolysates thereof.

This and other objects will be made apparent by the followingdescription of the preferred embodiments and appended claims.

SUMMARY OF THE INVENTION

The present invention provides a method of treating Alzheimer's Disease,comprising the step of administering to a subject a symptom-alleviatingdose of a compound, selected from the group consisting of phytic acid, aphytate salt, an isomer or hydrolysate of phytic acid or a phytate salt,or a mixture of any combination thereof. The preferred method ofadministration is by the oral route.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The method according to the present invention comprises treating asubject, afflicted with Alzheimer's Disease, with a composition in whichthe active ingredient is phytic acid, a phytate salt, or an isomer orhydrolysate of phytic acid or phytate salt. By the term isomer as usedherein, it is intended to include the various conformations of phyticacid, as described hereinabove, and the corresponding conformations ofphytate salts. The term salts is broadly intended to cover any of thevarious salts formed by the replacement of any or all of the availableacidic protons of the phosphate groups with a counterion. The counterionmay be any pharmaceutically acceptable counterion such as sodium,magnesium, potassium, zinc, ferric, ferrous, and the like, includingorganic counterions such as quaternary ammonium ions and ions of organicbases.

The present invention also includes the hydrolysates of phytic acid andphytate salts wherein one or more of the phosphate groups have beenremoved. Once administered into the digestive tract, bloodstream, thephytic acid or phytate salt may be hydrolyzed by digestive, blood orcellular enzymes, thereby removing one or more of the phosphate groupson the cyclohexane ring. However, it is contemplated to be within thescope of the invention that these hydrolysates of phytic acid andphytate salts may also be administered directly to the subject andtherefore are within the scope of the present invention.

The hydrolysates of phytic acid and phytate salts may be prepared bypartial acid or basic hydrolysis or by hydrolysis using enzymes prior topreparation of dosage forms for administration. Preferably, thehydrolysates will be made in vivo by coadministering with phytic acid orphytate salt an enzyme which hydrolyzes phosphate groups, such as3-phytase, 6-phytase or acid phosphatase.

The phytic acid or phytate salt may be absorbed into or adsorbed onto asolid carrier to facilitate pharmaceutical administration. For example,phytic acid may be formulated into a starch powder by spray drying orvacuum drying an aqueous mixture of phytic acid and dextrin.

The preferred compositions for administration, particularly in oraldosage form, are the mono-, di-potassium phytate salts and mixturesthereof which may be prepared from commercially and readily availablesodium phytate by initially removing the sodium using ion exchangechromatography on a suitable resin, such as Dowex beads. The free phyticacid may then be treated with potassium hydroxide to convert to themono- and di-potassium phytate salt.

The preferred method of administration of the compositions according tothe present invention is through oral administration in liquid or tabletform. As described hereinabove, the compositions may be administered aspharmaceutically acceptable salts such as salts with alkali metalcations (sodium, potassium, lithium), ammonium salts and salts withorganic bases such as piperidine, triethanolamine,diethylaminoethylamine salts, and the like.

In addition to the active ingredients, the composition may also containan effective proportion, usually from 0.001 to 0.1% weight by volume, ofa pharmaceutically acceptable preservative or sterilizing agent such ascetyl pyridinium chloride, tetradecyltrimethyl ammonium bromide(commercially known as Centramide), benzyl dimethyl[2-(2-)p-(1,1,3,3-tetramethyl butyl)) phenoxy) ethoxy] ammonium chloride(known commercially as Benzethonium Chloride) andmyristyl-gamma-picolinium chloride.

The pharmaceutical composition may also contain conventional excipients,e.g., sodium chloride, dextrose, mannitol, and buffers such as sodiumdihydrogen ortho phosphate, disodium hydrogen phosphate, sodiumcitrate/citric acid, and boric acid/sodium borate. The proportion andconcentration of excipients and buffers may be varied within fairly wideranges, providing the resulting solution is stable and nonirritatingwhen administered. The preferred method of administration is by oraladministration as a solid compound. The composition may be prepared inthe conventional manner as tablets, pills or powders, using conventionalcarriers.

The dosage to be administered will vary with the severity of thediseased condition. However, in general, particularly for oraladministration, oral administration of from 1/2 to 3 grams of phyticacid (or equivalent phytate salt, isomer or hydrolysate) per kilogram ofbody weight in the diet per day will usually be effective. Frequency ofdosage administration may, of course, be varied as needed and asdiscretionarily required by the attending physician.

For oral administration, in a preferred embodiment, the activeingredient of the composition will also contain an enzyme such as3-phytase (EC 3.1.38), 6-phytase (EC 3.1.3.26) or acid phosphatasewhich, when exposed to the digestive tract, will assist in hydrolyzingone or more of the phosphate groups from the active ingredient. Sincephytic acid or phytate salts are not naturally present in animals, thedigestive enzymes in animals are believed to be insufficient tocompletely hydrolyze the phosphate groups. Therefore, to enhance thehydrolysis of the phosphate groups in an animal or man, it is preferredthat the active ingredient be administered with one or more of theaforementioned enzymes, with the preferred enzyme being 3-phytase (EC3.1.38).

I claim:
 1. A method of treating Alzheimer's Disease comprising the stepof orally administering to a subject a dephosphorylating enzyme and asymptom-alleviating amount equivalent to a daily dosage of about 0.5-3grams of phytic acid per kilogram of body weight per day of a compoundselected from the group consisting of phytic acid, a phytate salt, anisomer or hydrolysate of phytic acid or a phytate salt, or a mixture oftwo or more thereof whereby the amount of enzyme present is sufficientto hydrolyze the phytic acid.
 2. A method according to claim 1 whereinsaid enzyme is 3-phytase, 6-phytase, acid phosphatase, or a mixture oftwo or more thereof.
 3. A method according to claim 2 wherein saidenzyme is 3-phytase EC 3.1.38.